Synthesis, biological evaluation and molecular modeling study of pyrazole and pyrazoline derivatives as selective COX-2 inhibitors and anti-inflammatory agents. Part 2 (original) (raw)
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Bioorganic Chemistry, 2019
New pyrazoles and pyrazolo[3,4-b] pyridines were synthesized and their structure was confirmed by elemental analyses as well as IR, 1 H NMR, 13 C NMR, and mass spectral data. All the newly synthesized derivatives were evaluated in vitro for inhibitory activity against COX-1 and COX-2 enzymes and their IC 50 values were calculated, most of the derivatives showed good inhibitory activity with derivatives IVb, IVh and IVJ showing inhibitory activity better than celecoxib. Moreover, the eight most potent derivatives IVa, IVb, IVc, IVd, IVe, IVh, IVJ, and IVL were selected for in vivo assay to measure their effect on paw edema in rates and their ulcerogenic effect. Compounds IVa, IVb and IVc were found to be the most active and selective as COX-2 inhibitors and most effective in protection from edema, they were also found to have lowest ulcerogenic effect among all derivatives. 7.54-7.98 ppm of the (NH 2) group. It also confirmed the structure of (Ve and Vf) by the D 2 O exchangeable signal at 9.97 of (OH) group and singlet signal at 3.86 ppm of methoxy group. 13 C NMR showed signal equivalent to (CN) group at 75.69 and 75.46 ppm. Also the signal at 55.76ppm equivalent to (OCH 3) group of (Vf). Mass spectroscopy showed molecular ion peak of all derivatives. 2.2.Biological activity 2.2.1. In vitro COX-1 and COX-2 assay: All newly synthesized compounds were subjected to in vitro COX-1 and COX-2 assay, the eight most potent derivatives were subjected to in vivo anti-inflammatory screening and ulcerogenic effect. First, the structure of the new derivatives was designed to follow structure activity relationship of celecoxib a selective COX-2 enzyme inhibitor [21] COX-2 enzyme shows larger space than COX-1 and so the bulkier inhibitors fit better to COX-2 showing selectivity [22]. Derivatives (IVa-L) were the bulkier among other derivatives and so showed highest activity with IVb, IVh and IVJ showing activity better than celecoxib with IC 50 values of 0.048, 0.048 and 0.046 µM respectively compared to IC 50 value of celecoxib 0.049 µM. while, IVa, IVc, IVd, IVe, IVf, IVg, IVL and Vf showed moderate activity relative to celecoxib with IC 50 values 0.071, 0.055, 0.051, 0.067, 0.082. 0.093, 0.054 and 0.082 µM respectively but still more potent than NSAID drugs indomethacin and diclofenac sodium. From these results, the bulkier derivatives showed better activity than the less bulky ones. Highlights This paper describes the synthesis of new pyrazoles and pyrozolo [3,4-b] pyridines. The new derivatives were evaluated for COX-1, COX-2 inhibitory activities and antiinflammatory activity. Their safety was examined by their ulcerogenic effect Some derivatives showed potent activity compared to celecoxib and indomethacin,
CBDD, 2014
The present study reported the synthesis and biologic evaluation of new pyrazolone derivatives for COX-2 inhibitory activities and investigated in vivo for their anti-inflammatory activities using carrageenan-induced rat paw edema model as well as in vitro using HRBC membrane stabilization and protein denaturation method. Eight derivatives showed pronounced COX-2 inhibition, and 5a, 5d, and 5f exhibited the highest COX-2 inhibition. The derivatives were further evaluated for antioxidant activity wherein 5a and 5b showed potent free radical-scavenging activity against DPPH, nitric oxide, and hydrogen peroxide radicals. Molecular docking study revealed the binding orientations of pyrazolone derivatives into the active sites of COX-2 and thereby helps to design the potent inhibitors.
Journal of Chemistry
Series of diaryl-based pyrazole and triazole derivatives were designed and synthesized in a facile synthetic approach in order to produce selective COX-2 inhibitor. These series of derivatives were synthesized by different reactions like Vilsmeier–Haack reaction and click reaction. In vitro COX-1 and COX-2 inhibition studies showed that five compounds were potent and selective inhibitors of the COX-2 isozyme with IC50 values in 0.551–0.002 μM range. In the diarylpyrazole derivatives, compound 4b showed the best inhibitory activity against COX-2 with IC50 = 0.017 μM as one of the N-aromatic rings was substituted with sulfonamide and the other aromatic ring was unsubstituted. However, when the N-aromatic ring was substituted with sulfonamide and the other aromatic ring was substituted with sulfone (compound 4d), best COX-2 selectivity was achieved (IC50 = 0.098 μM, SI = 54.847). In the diaryltriazole derivatives, compound 15a showed the best inhibitory activity in comparison to all sy...
European Journal of Medicinal Chemistry, 2014
A novel series of 2-phenyl-5-(1,3-diphenyl-1H-pyrazol-4-yl)-1,3,4-oxadiazoles were designed and synthesized for selective COX-2 inhibition with potent anti-inflammatory activity. Among the compounds tested, 9g (2-(3-(4-nitrophenyl)-1-phenyl-1H-pyrazol-4-yl)-5-phenyl-1,3,4-oxadiazole) was found to be the most potent inhibitor of COX-2 with IC 50 of 0.31 mM showing promising degree of anti-inflammatory activity in the carrageenan-induced rat paw edema model with ED 50 of 74.3 mg/kg. The lead compound 9g further showed suppression of acetic acid-induced writhes comparable to that of aspirin and gastrosparing profile superior to the aspirin. Molecular docking analysis displayed higher binding affinity of ligands towards COX-
Bioorganic & Medicinal Chemistry, 2011
New arylhydrazone derivatives and a series of 1,5-diphenyl pyrazoles were designed and synthesized from 1-(4-chlorophenyl)-4,4,4-trifuorobutane-1,3-dione 1. The newly synthesized compounds were investigated in vivo for their anti-inflammatory activities using carrageenan-induced rat paw oedema model. Moreover, they were tested for their inhibitory activity against ovine COX-1 and COX-2 using an in vitro cyclooxygenase (COX) inhibition assay. Some of the new compounds (2f, 6a and 6d) showed a reasonable in vitro COX-2 inhibitory activity, with IC 50 value of 0.45 lM and selectivity index of 111.1. A virtual screening was carried out through docking the designed compounds into the COX-2 binding site to predict if these compounds have analogous binding mode to the COX-2 inhibitors. Docking study of the synthesized compounds 2f, 6a and 6d into the active site of COX-2 revealed a similar binding mode to SC-558, a selective COX-2 inhibitor.
A new series of triarylpyrazoline derivatives 8a–p containing the most important COX-2 pharmacophore (SO 2 CH 3 or/and SO 2 NH 2) were synthesized by reaction of propen-1-one derivatives 6a–h with different phenyl hydrazine hydrochloride derivatives 7a–b in aqueous ethanol. All prepared compounds were evaluated for their in vitro COX-1/COX-2 inhibitory activity and the in vivo anti-inflammatory activity. All compounds were more selective for COX-2 isozyme than COX-1 isozyme and showed good in vivo anti-inflammatory activity. Compounds 8g, 8j and 8o showed the highest anti-inflammatory activity and were less ulcerogenic (Ulcer Index = 6.85, 7.7, 5.92, respectively) than indomethacin (Ulcer Index = 12.3) and comparable to celecoxib (Ulcer Index = 4.85).
Archiv der Pharmazie, 2009
The pyrazolo [3,4-d]pyrimidine system shows a multitude of interesting pharmacological properties. Owing to the potential anti-inflammatory activity of 5-benzamido-pyrazolo[3,4-d]pyrimidin-4-one derivatives and considering the easy synthesis of this class of compounds, a set of new 5benzamido-1H-pyrazolo[3,4-d]pyrimidin-4-ones has been prepared in 42-80% yields by reacting 5aminopyrazole-4(N-benzoyl)carbohydrazide derivatives and the opportune triethylorthoesters. Compounds 8a, b, 10a -d, and 11a, b revealed a superior inhibitory profile against COX-2, when compared to that of reference standards NS398 and indomethacin. Molecular modelling studies confirmed the obtained biological results. Figure 1. Structurally related pyrazolo[3,4-d]pyrimidine 1 and 4(3H)-quinazolinone 2 nuclei.
Journal of Medicinal Chemistry, 1997
A series of sulfonamide-containing 1,5-diarylpyrazole derivatives were prepared and evaluated for their ability to block cyclooxygenase-2 (COX-2) in vitro and in vivo. Extensive structureactivity relationship (SAR) work was carried out within this series, and a number of potent and selective inhibitors of COX-2 were identified. Since an early structural lead (1f, SC-236) exhibited an unacceptably long plasma half-life, a number of pyrazole analogs containing potential metabolic sites were evaluated further in vivo in an effort to identify compounds with acceptable pharmacokinetic profiles. This work led to the identification of 1i (4-[5-(4methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide, SC-58635, celecoxib), which is currently in phase III clinical trials for the treatment of rheumatoid arthritis and osteoarthritis.